Epilepsies in Children with 2q24.3 Deletion/Duplication

Abstract

The chromosome 2q24.3 region appears to be important in childhood epilepsy and contains three genes encoding a sodium channel, which are involved in the disorder (SCN1A, SCN2A, and SCN3A). There have been several reports indicating an association between epilepsy and 2q24.3 deletion or duplication. Epilepsy phenotypes markedly differ between patients with 2q24.3 deletion and those with duplication. The majority of patients with 2q24.3 deletion are characterized by severe epilepsy phenotypes such as Dravet syndrome or Dravet syndrome–like intractable epilepsy, which onsets during infancy. This is particularly applicable to patients with SCN1A deletion. In addition, facial dysmorphism (and other dysmorphic features) is observed in all patients with 2q24.3 deletion–associated epilepsy. SCN1A contributes to epileptogenicity; several other genes involved in the deleted region may also play a role in dysmorphism. In all reported cases, patients with 2q24.3 duplication had neonatal- or infantile-onset epilepsy. Although these patients typically experienced multiple daily seizures, seizures were controlled by the appropriate antiepileptic treatment in the majority of cases. SCN2A and SCN3A were duplicated in all patients and are presumed to contribute to epileptogenicity. Facial or other dysmorphic features were infrequent in patients with 2q24.3 duplication. Array comparative genomic hybridization should be considered in patients with neonatal- or infantile-onset epilepsy, because information obtained using this method is likely to be instructive in diagnosis, prognostication, and treatment regimen decisions.

Keywords

sodium channel genes - dysmorphic features - Dravet syndrome - array comparative genomic hybridization

• References

• 1 Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 2001; 68 (6) 1327-1332
• 2 Wallace RH, Scheffer IE, Barnett S , et al. Neuronal sodium-channel alpha1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 2001; 68 (4) 859-865
• 3 Harkin LA, McMahon JM, Iona X , et al; Infantile Epileptic Encephalopathy Referral Consortium. The spectrum of SCN1A-related infantile epileptic encephalopathies. Brain 2007; 130 (Pt 3) 843-852
• 4 Shi X, Yasumoto S, Nakagawa E, Fukasawa T, Uchiya S, Hirose S. Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. Brain Dev 2009; 31 (10) 758-762
• 5 Shi X, Yasumoto S, Kurahashi H , et al. Clinical spectrum of SCN2A mutations. Brain Dev 2012; 34 (7) 541-545
• 6 Heron SE, Crossland KM, Andermann E , et al. Sodium-channel defects in benign familial neonatal-infantile seizures. Lancet 2002; 360 (9336) 851-852
• 7 Nakamura K, Kato M, Osaka H , et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 2013; 81 (11) 992-998
• 8 Holland KD, Kearney JA, Glauser TA , et al. Mutation of sodium channel SCN3A in a patient with cryptogenic pediatric partial epilepsy. Neurosci Lett 2008; 433 (1) 65-70
• 9 Vanoye CG, Gurnett CA, Holland KD, George Jr AL, Kearney JA. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol Dis 2014; 62: 313-322
• 10 Madia F, Striano P, Gennaro E , et al. Cryptic chromosome deletions involving SCN1A in severe myoclonic epilepsy of infancy. Neurology 2006; 67 (7) 1230-1235
• 11 Pescucci C, Caselli R, Grosso S , et al. 2q24-q31 deletion: report of a case and review of the literature. Eur J Med Genet 2007; 50 (1) 21-32
• 12 Davidsson J, Collin A, Olsson ME, Lundgren J, Soller M. Deletion of the SCN gene cluster on 2q24.4 is associated with severe epilepsy: an array-based genotype-phenotype correlation and a comprehensive review of previously published cases. Epilepsy Res 2008; 81 (1) 69-79
• 13 Chen CP, Lin SP, Chern SR , et al. Array-CGH detection of a de novo 2.8 Mb deletion in 2q24.2—>q24.3 in a girl with autistic features and developmental delay. Eur J Med Genet 2010; 53 (4) 217-220
• 14 Krepischi AC, Knijnenburg J, Bertola DR , et al. Two distinct regions in 2q24.2-q24.3 associated with idiopathic epilepsy. Epilepsia 2010; 51 (12) 2457-2460
• 15 Takatsuki S, Nakamura R, Haga Y , et al. Severe pulmonary emphysema in a girl with interstitial deletion of 2q24.2q24.3 including ITGB6. Am J Med Genet A 2010; 152A (4) 1020-1025
• 16 Magri C, Piovani G, Pilotta A, Michele T, Buzi F, Barlati S. De novo deletion of chromosome 2q24.2 region in a mentally retarded boy with muscular hypotonia. Eur J Med Genet 2011; 54 (3) 361-364
• 17 Bartnik M, Chun-Hui Tsai A, Xia Z, Cheung SW, Stankiewicz P. Disruption of the SCN2A and SCN3A genes in a patient with mental retardation, neurobehavioral and psychiatric abnormalities, and a history of infantile seizures. Clin Genet 2011; 80 (2) 191-195
• 18 Nimmakayalu M, Noble N, Horton VK , et al. 2q24 deletions: further characterization of clinical findings and their relation to the SCN cluster. Am J Med Genet A 2012; 158A (11) 2767-2774
• 19 Traylor RN, Dobyns WB, Rosenfeld JA , et al. Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions. Mol Syndromol 2012; 3 (3) 102-112
• 20 Celle ME, Cuoco C, Porta S, Gimelli G, Tassano E. Interstitial 2q24.3 deletion including SCN2A and SCN3A genes in a patient with autistic features, psychomotor delay, microcephaly and no history of seizures. Gene 2013; 532 (2) 294-296
• 21 Belengeanu V, Gamage TH, Farcas S , et al. A de novo 2.3 Mb deletion in 2q24.2q24.3 in a 20-month-old developmentally delayed girl. Gene 2014; 539 (1) 168-172
• 22 Lazier J, Chernos J, Lowry RB. A 2q24.3q31.1 microdeletion found in a patient with Filippi-like syndrome phenotype: a case report. Am J Med Genet A 2014; 164A (9) 2385-2387
• 23 Zuberi SM, Brunklaus A, Birch R, Reavey E, Duncan J, Forbes GH. Genotype-phenotype associations in SCN1A-related epilepsies. Neurology 2011; 76 (7) 594-600
• 24 Suls A, Claeys KG, Goossens D , et al. Microdeletions involving the SCN1A gene may be common in SCN1A-mutation-negative SMEI patients. Hum Mutat 2006; 27 (9) 914-920
• 25 Bureau M, Dalla Bernardina B. Electroencephalographic characteristics of Dravet syndrome. Epilepsia 2011; 52 (Suppl. 02) 13-23
• 26 Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome. Epilepsia 2011; 52 (Suppl. 02) 44-49
• 27 Akiyama M, Kobayashi K, Yoshinaga H, Ohtsuka Y. A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 2010; 51 (6) 1043-1052
• 28 Oguni H, Hayashi K, Awaya Y, Fukuyama Y, Osawa M. Severe myoclonic epilepsy in infants—a review based on the Tokyo Women's Medical University series of 84 cases. Brain Dev 2001; 23 (7) 736-748
• 29 Okumura A, Uematsu M, Imataka G , et al. Acute encephalopathy in children with Dravet syndrome. Epilepsia 2012; 53 (1) 79-86
• 30 Watanabe K, Okumura A. Benign partial epilepsies in infancy. Brain Dev 2000; 22 (5) 296-300
• 31 Okumura A, Watanabe K, Negoro T , et al. Long-term follow-up of patients with benign partial epilepsy in infancy. Epilepsia 2006; 47 (1) 181-185
• 32 Li BM, Liu XR, Yi YH , et al. Autism in Dravet syndrome: prevalence, features, and relationship to the clinical characteristics of epilepsy and mental retardation. Epilepsy Behav 2011; 21 (3) 291-295
• 33 O'Roak BJ, Deriziotis P, Lee C , et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 2011; 43 (6) 585-589
• 34 O'Roak BJ, Vives L, Girirajan S , et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012; 485 (7397) 246-250
• 35 Han S, Tai C, Westenbroek RE , et al. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission. Nature 2012; 489 (7416) 385-390
• 36 Sanders SJ, Murtha MT, Gupta AR , et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485 (7397) 237-241
• 37 Jiang YH, Yuen RK, Jin X , et al. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet 2013; 93 (2) 249-263
• 38 Heron SE, Scheffer IE, Grinton BE , et al. Familial neonatal seizures with intellectual disability caused by a microduplication of chromosome 2q24.3. Epilepsia 2010; 51 (9) 1865-1869
• 39 Raymond G, Wohler E, Dinsmore C , et al. An interstitial duplication at 2q24.3 involving the SCN1A, SCN2A, SCN3A genes associated with infantile epilepsy. Am J Med Genet A 2011; 155A (4) 920-923
• 40 Okumura A, Yamamoto T, Shimojima K , et al. Refractory neonatal epilepsy with a de novo duplication of chromosome 2q24.2q24.3. Epilepsia 2011; 52 (7) e66-e69
• 41 Vecchi M, Cassina M, Casarin A , et al. Infantile epilepsy associated with mosaic 2q24 duplication including SCN2A and SCN3A. Seizure 2011; 20 (10) 813-816
• 42 Goeggel Simonetti B, Rieubland C, Courage C , et al. Duplication of the sodium channel gene cluster on 2q24 in children with early onset epilepsy. Epilepsia 2012; 53 (12) 2128-2134
• 43 Lim BC, Min BJ, Park WY , et al. A unique phenotype of 2q24.3-2q32.1 duplication: early infantile epileptic encephalopathy without mesomelic dysplasia. J Child Neurol 2014; 29 (2) 260-264